Extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof

ABSTRACT

An extended release tablet formulation comprising pramipexole or a pharmaceutically acceptable salt thereof in a matrix, the matrix comprising at least two water swelling polymers, wherein one of the polymers is pregelatinized starch, and wherein another one of the polymers is an anionic polymer.

RELATED APPLICATIONS

This application claims priority to European Application No. 04019248.6filed Aug. 13, 2004, which is hereby incorporated by reference in itsentirety.

FIELD OF THE INVENTION

The present invention is directed to an extended release tabletformulation containing pramipexole or a pharmaceutically acceptable saltthereof, method for manufacturing the same, and use thereof.

BACKGROUND OF THE INVENTION

Pramipexole is a known dopamine D2 receptor agonist. It is structurallydifferent from the ergot-derived drugs, e.g., bromocriptine orpergolide. It is also pharmacologically unique in that it is a fullagonist and has receptor selectivity for the dopamine D2 family ofdopamine receptors.

Pramipexole is designated chemically as(S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole and has themolecular formula C₁₀H₁₇N₃S and a relative molecular mass of 211.33. Thechemical formula is as follows:

The salt form commonly used is pramipexole dihydrochloride monohydrate(molecular formula C₁₀H₂₁Cl₂N₃OS; relative molecular mass 302.27).Pramipexole dihydrochloride monohydrate is a white to off-white,tasteless, crystalline powder. Melting occurs in the range of 296° C. to301° C., with decomposition. Pramipexole is a chiral compound with onechiral center. Pure (S)-enantiomer is obtained from the syntheticprocess by chiral recrystallization of one of the intermediates duringsynthesis.

Pramipexole dihydrochloride monohydrate is a highly soluble compound.Water solubility is more than 20 mg/mL and solubility in buffer media isgenerally above 10 mg/mL between pH 2 and pH 7.4. Pramipexoledihydrochloride monohydrate is not hygroscopic, and has a highlycrystalline nature. Under milling, the crystal modification(monohydrate) does not change. Pramipexole is very stable in the solidstate, yet in solution it is light sensitive.

Pramipexole immediate release (IR) tablets were first authorized in theUSA in 1997, followed over the course of the next years by marketingauthorizations in the European Union (EU), Switzerland, Canada, andSouth America as well as in countries in Eastern Europe, the Near East,and Asia.

Pramipexole IR tablets are indicated in the EU and US for the treatmentof signs and symptoms of either early Parkinson's Disease or advancedParkinson's Disease in combination with levodopa. The IR tablets have tobe taken 3 times a day.

From the pharmacokinetic point of view, pramipexole IR tablets arerapidly and completely absorbed following oral administration. Theabsolute bioavailability is greater than 90% and the maximum plasmaconcentration occurs within 1 to 3 hours. The rate of absorption isreduced by food intake but not the overall extent of absorption.Pramipexole shows linear kinetics and a relatively small inter-patientvariation of plasma levels. The elimination half-life (t_(1/2)[h])varies from 8 hours in the young to 12 hours in the elderly.

As commonly known, modified release of active ingredient(s) allowssimplification of the patient's administration scheme by reducing theamount of recommended daily intakes, improves patient's compliance, andattenuates adverse events, e.g., related to high plasma peaks. Modifiedrelease pharmaceutical preparations regulate the release of theincorporated active ingredient or ingredients over time and compriseformulations with a controlled, a prolonged, a sustained, a delayed, aslow or an extended release, so they accomplish therapeutic orconvenience objectives not offered by conventional dosage forms such assolutions or promptly dissolving dosage forms.

A modified or extended release of active ingredient(s) from apharmaceutical preparation may be accomplished by homogeneouslyembedding the active ingredient(s) in a hydrophilic matrix, being asoluble, partially soluble or insoluble network of viscous, hydrophilicpolymers, held together by physical or chemical entanglements, by ionicor crystalline interactions, by complex formation, by hydrogen bonds orvan der Waals forces. The hydrophilic matrix swells upon contact withwater, thereby creating a protective gel layer from which the activeingredient(s) is (are) slowly, gradually, continuously released in timeeither by diffusion through the polymeric network, by erosion of the gellayer, by dissolution of the polymer, or by a combination of theserelease mechanisms.

However, it has proved difficult to formulate a tablet having a suitablecombination of modified, extended or sustained-release and handlingproperties, where the drug is one having relatively high solubility, asin the case of pramipexole dihydrochloride.

There are a number of approaches described in prior art to providesustained release tablet compositions of pramipexole.

WO 2004/010997 describes a sustained-release pharmaceutical compositionin a form of an orally deliverable tablet comprising a water-solublesalt of pramipexole, dispersed in a matrix comprising a hydrophilicpolymer and a starch having a tensile strength of at least about 0.15 kNcm⁻², preferably at least about 0.175 kN cm⁻², and more preferably atleast about 0.2 kN cm⁻², at a solid fraction representative of thetablet. The disclosure thereof is concentrated to provide a compositionwith sufficient hardness yield during a high-speed tabletting operation,in particular to resist erosion during application of a coating layer.According to a preferred embodiment it is provided a pharmaceuticalcomposition in a form of an orally deliverable tablet having a corecomprising pramipexole dihydrochloride monohydrate in an amount of about0.375, 0.75, 1.5, 3, or 4.5 mg, dispersed in a matrix comprising (a)HPMC type 2208 in an amount of about 35% to about 50% by weight of thetablet and (b) a pregelatinized starch having a tensile strength of atleast about 0.15 kN cm⁻² at a solid fraction of 0.8, in an amount ofabout 45% to about 65% by weight of the tablet; the core beingsubstantially enclosed in a coating that constitutes about 2% to about7% of the weight of the tablet, the coating comprising an ethylcellulose-based hydrophobic or water-insoluble component and anHPMC-based pore-forming component in an amount of about 10% to about 40%by weight of the ethyl cellulose-based component.

Furthermore, WO 2004/010999 discloses an orally deliverablepharmaceutical composition comprising a therapeutically effective amountof pramipexole or a pharmaceutically acceptable salt thereof and atleast one pharmaceutically acceptable excipient, the compositionexhibiting at least one of (a) an in vitro release profile wherein onaverage no more than about 20% of the pramipexole is dissolved within 2hours after placement of the composition in a standard dissolution test;and (b) an in vivo pramipexole absorption profile following single doseoral administration to healthy adult humans wherein the time to reach amean of 20% absorption is greater than about 2 hours and/or the time toreach a mean of 40% absorption is greater than about 4 hours. However,in practical use, it appears that any formulation having an extended orcontrolled release profile designed for a once daily application wouldmeet the above requirements for which a general teaching how to adjustsuch a profile is missing.

It is an object of the present invention to provide a controlled releasetablet composition of pramipexole or a pharmaceutically acceptable saltthereof that is suitable for once-daily oral administration. It is afurther object to provide a tablet composition comprising pramipexole ora pharmaceutically acceptable salt thereof that provides a day-longtherapeutic effect and will allow patients to treat their symptoms witha single daily dose, which makes it possible to adjust the releaseprofile of the active ingredient according to a selected release profiledependent or independent from the pH values. Furthermore a method ofmanufacturing the tablet formulation shall be provided.

DESCRIPTION OF THE INVENTION

Surprisingly, it has been found that pramipexole or a pharmaceuticallyacceptable salt thereof may be used in formulations as once dailyextended (or slow) release tablets and two alternative formulationprinciples allow different release rate types dependent or independentfrom the pH value.

One embodiment of the present invention relates to an extended releasetablet formulation comprising pramipexole or a pharmaceuticallyacceptable salt thereof in a matrix, the matrix comprising at least twowater swelling polymers, wherein one of the polymers is pregelatinizedstarch, and wherein another one of the polymers is an anionic polymer.

Preferably the invention relates to an extended release tabletformulation, wherein the anionic polymer is selected from the group ofoptionally crosslinked acrylic acid polymers, methacrylic acid polymers,alginates and carboxy methyl cellulose.

Also preferred is an extended release tablet formulation, wherein theanionic polymer is a crosslinked acrylic acid polymer and wherein thecontent of the optionally crosslinked acrylic acid polymer in the matrixis from about 0.25 wt.-% to about 25 wt.-%, and preferably from about0.5 wt.-% to about 15 wt.-%, and preferably from about 1 wt.-% to about10 wt.-%.

Also preferred is an extended release tablet formulation furthercomprising a water swelling polymer which is not pregelatinized starchor an anionic polymer and which is preferably selected fromhydroxypropylcellulose or hydroxypropyl methyl cellulose.

Particularly preferred is an extended release tablet formulation,wherein the water swelling polymer which is not pregelatinized starch oran anionic polymer is hydroxypropyl methyl cellulose and wherein thecontent of hydroxypropyl methyl cellulose in the matrix is from about 10wt.-% to about 75 wt.-%, and preferably from about 25 wt.-% to about 65wt.-%.

Particularly preferred is an extended release tablet formulation,wherein the matrix comprises about:

-   -   (a) 0.05 to 5 wt.-% of pramipexole or a salt thereof;    -   (b) 0.25 to 25 wt.-% of anionic water swelling polymer(s);    -   (c) 10 to 75 wt.-% of water swelling polymer(s) other than (b);        and    -   (d) to 100 wt.-% of further excipients

Another embodiment of the present invention relates to an extendedrelease tablet formulation comprising pramipexole or a pharmaceuticallyacceptable salt thereof in a matrix comprising:

-   -   a) at least pregelatinized starch as water swelling polymer and        optionally excipients, the resulting tablet providing a        pH-independent in vitro release characteristic in the range from        pH 1 to 7.5, or    -   b) at least pregelatinized starch as water swelling polymer, a        water swelling anionic polymer, preferably an acrylic acid        polymerisate, and optionally excipients, the resulting tablet        providing a pH-dependent release characteristic with a faster        release characteristic in the range of pH<4.5, and a slower and        further on pH-independent release characteristic in the range        from pH 4.5 to 7.5.

The extended release formulations according to the present inventionintended for oral administration allow to select and estimate which invitro release characteristic and timing of a formulation is mostsuitable to achieve the desired in vivo plasma profiles preferably witha once daily application. Therefore, two different formulationprinciples have been developed for a single unit matrix tablet, i.e.,two formulation principles having different release rate types areprovided and a different pH dependency is available. These alternativeformulations are beneficial to patients as the extended release drugdelivery will allow patients to treat their symptoms with a single dailydose, thereby increasing patient convenience and compliance.

The term “in vitro release characteristic” as used hereinbefore orhereinafter is directed to a release characteristic as obtained in akind of normally used liquid medium for in vitro experiments wherein therelease of active ingredient from the extended release formulation canoccur, i.e., for example, in in vitro dissolution media, but also inbody fluids or simulated body fluids, more in particular in thegastrointestinal fluids.

In the frame of the present invention the term “extended” release shouldbe understood in contrast to an immediate release, the active ingredientis gradually, continuously liberated over time, sometimes slower orfaster, dependent or independent from the pH value. In particular, theterm indicates that the formulation does not release the full dose ofthe active ingredient immediately after oral dosing and that theformulation allows a reduction in dosage frequency, following thedefinition for extended release, interchangeable with slow release. Aslow or extended release, used synonymously with prolonged action,sustained release, or modified release, dosage form is a dosage formthat allows at least a reduction in dosing frequency or a significantincrease in patient compliance or therapeutic performance as compared tothat presented as a conventional dosage form (e.g., as a solution or animmediate drug-releasing, conventional solid dosage form).

A release characteristic which is pH-independent indicates that therelease characteristic is virtually the same in different pH media.

According to the teaching of the present invention two types of extendedrelease tablet formulations are available showing different in vitrorelease profiles.

The extended release tablets of the present invention apply a swellingand partly eroding polymer matrix leading to a square root of time toexponential in vitro release characteristic, formulation a) is widelyindependent from the pH value in the range from pH 1 to 7.5, andformulation b) is (slightly) faster in simulated gastric juice having apH<4.5 but is independent from the pH value in the range from 4.5 to7.5. A faster release in simulated gastric juice versus slower releasein the intestinal fluid can be advantageous in cases where a loadingdose effect from the dosage form is desired, whereas a widely pHindependent release profile can be advantageous to reduce the risk ofdose dumping and food effects.

According to the present invention under “formulation a)” is understoodthe tablet formulation wherein the matrix comprises the composition asabove-defined under a) and under “formulation b)” is understood thetablet formulation wherein the matrix comprises the composition asabove-defined under b).

The water swelling polymer present in both alternate tablet formulationsa) and b) of the present invention represents at least pregelatinizedstarch as one hydrophilic water swelling polymer constituting theextended release matrix which slowly releases the pramipexole or itssalt as active ingredient. The polymer swells upon contact with aqueousfluid following administration, resulting in a viscous, drug releaseregulating gel layer.

Examples of polymers present in the formulation of the invention inaddition to pregelatinized starch are water swelling substantiallyneutral polymers or water swelling anionic polymers.

The term “water swelling substantially neutral polymers” of the presentinvention comprises alkylcelluloses, such as, methyl cellulose;hydroxyalkylcelluloses, for example, hydroxy methyl cellulose,hydroxyethyl cellulose, hydroxypropylcellulose and hydroxybutylcellulose; hydroxyalkyl alkylcelluloses, such as hydroxyethyl methylcellulose and hydroxypropyl methyl cellulose; carboxyalkylcelluloseesters; other natural, semi-synthetic, or synthetic di-, oligo-, andpolysaccharides such as galactomannans, tragacanth, agar, guar gum, andpolyfructans; methacrylate copolymers; polyvinyl alcohol;polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinylacetate; combinations of polyvinyl alcohol and polyvinylpyrrolidone;polyalkylene oxides such as polyethylene oxide and polypropylene oxideand copolymers of ethylene oxide and propylene oxide, preferablycellulose ether derivatives such as hydroxypropyl methyl cellulose andhydroxypropyl cellulose, most preferred hydroxypropyl methyl cellulose.

The term “water swelling anionic polymer” of the present inventioncomprises acrylic acid polymerisate, methacrylic acid copolymers,alginates, carrageenans, acacia, xanthan gum, chitin derivates such aschitosan, carmellose sodium, and carmellose calcium, preferably acrylicacid polymerisate.

Different viscosity grades of hydroxypropyl cellulose and hydroxypropylmethyl cellulose are commercially available. Hydroxypropyl methylcellulose (HPMC) preferably used in the present invention has aviscosity grade ranging from about 3,500 mPa.s to about 100,000 mPa.s,in particular ranging from about 4,000 mPa.s to about 20,000 mPa.s andmost in particular a viscosity grade of about 6,500 mPa.s to about15,000 mPa.s (apparent viscosity of a 2% aqueous solution at 20° C.),e.g., hypromellose 2208 or 2206 (DOW, Antwerp, Belgium). HPMC type 2208contains 19-24% by weight methoxy and 4-12% by weight hydroxypropoxysubstituents.

Hydroxypropyl cellulose having a viscosity higher than 1,500 mPa.s(apparent viscosity of a 1% aqueous solution at 20° C.) is preferred, inparticular hydroxypropyl cellulose having a viscosity in the range fromabout 1500 to about 3000 mPa.s, preferably from 4000 to 6500 mPa.s (2%aqueous solutions), e.g., the KLUCEL® series such as KLUCEL® M(Hercules, Wilmington, USA).

Without wishing to be bound by theory, there are believed to exist threemain mechanisms by which pramipexole or a salt thereof can be releasedfrom a hydrophilic matrix: dissolution, erosion and diffusion.Pramipexole or its salt will be released by the dissolution mechanismwhen it is homogeneously dispersed in a matrix network of a solublepolymer. The network will gradually dissolve in the gastrointestinaltract, thereby gradually releasing its load. The matrix polymer can alsogradually be eroded from the matrix surface, likewise releasingpramipexole or its salt in time. When pramipexole is processed in amatrix made up of an insoluble polymer, it will be released bydiffusion: the gastrointestinal fluids penetrate the insoluble,sponge-like matrix and diffuse back out loaded with drug.

Therefore, the water swelling polymers constituting the matrix, mainlyprovide for the controlled pharmacokinetic release profile of thepreparation. Depending on the amount of water swelling polymer(s)processed in the preparation, the release profile can be tuned, i.e.,larger amounts of swelling polymer lead to a more pronounced sustainedrelease effect and vice versa. Preferably, the amount of water swellingpolymer in the present formulation ranges from about 30 to about 99% byweight.

In addition, when using a combination of polymers, the ratio of thepolymers also influences the release profile of the preparation. Acombination of different polymers offers the possibility of combiningdifferent mechanisms by which pramipexole is released from the matrix.Such combination facilitates control of the pharmacokinetic releaseprofile of the preparation at will. For example, when using one or morewater swelling polymers, in particular hydroxypropyl cellulose andhydroxypropyl methyl cellulose, the weight percentage of hydroxypropylmethyl cellulose preferably ranges from 25 to about 62%; the weightpercentage of hydroxypropyl cellulose preferably ranges between about 0%and about 16%.

Release of pramipexole or a salt thereof from a matrix containinghydroxypropyl cellulose and hydroxypropyl methyl cellulose occurs by acombined set of release mechanisms. Due to the higher solubility ofhydroxypropyl methyl cellulose compared with hydroxypropyl cellulose,the former will gradually dissolve and erode from the matrix, whereasthe latter will more act as a sponge-like matrix former releasing theactive ingredient mainly by diffusion.

The extended release tablet formulation according to formulation a) ispH-independent. Therefore, the disadvantage that food relateddose-dumping may be encountered is avoided. The problem of food relateddose-dumping in fed patients can be attributed to a lot of factors suchas the mechanical forces that are exerted by the stomach on its contentand thus on an ingested preparation as well as the different pH regionsof the gastrointestinal tract. Since the pH values encountered in thegastrointestinal tract vary not only with the region of the tract, butalso with the intake of food, an extended release formulation preferablyalso has to provide an extended release profile and in particular has toavoid dose-dumping regardless whether the patient is in fasted or fedconditions.

According to the present invention the oral extended release formulationa) may retain its pharmacokinetic release profile along its way throughthe gastrointestinal tract so as to avoid undesirable fluctuations indrug plasma concentrations or complete dose-dumping, in particularavoids dose-dumping in different regions of the gastrointestinal tract.

Beside pramipexole or a salt thereof, and the water swelling polymers,the formulation of the present invention may also optionally comprisefurther excipients, i.e., pharmaceutically acceptable formulatingagents, in order to promote the manufacture, compressibility, appearanceand taste of the preparation. These formulating agents comprise, forexample, diluents or fillers, glidants, binding agents, granulatingagents, anti-caking agents, lubricants, flavors, dyes, andpreservatives. Other conventional excipients known in the art can alsobe included.

The filler may be selected from soluble fillers, for example, sucrose,lactose, in particular lactose monohydrate, trehalose, maltose,mannitol, sorbitol, inulin, and from insoluble fillers, for example,dicalcium or tricalcium phosphate and talc. Different grades of lactosecan be used. One type of lactose preferably used in the presentinvention is lactose monohydrate 200 mesh (DMV, Veghel, TheNetherlands). Another lactose monohydrate, lactose monohydrate of thetype DCL 11 (DMV, Veghel, The Netherlands), can also preferably be used.The notation DCL refers to “Direct Compression Lactose”. The number 11is a reference number of the manufacturer. In case of a water solubleactive ingredient, like the one described in this invention, morepreferably water insoluble fillers, such as starch and starch derivates,microcrystalline cellulose, dibasic calcium phosphate dihydrate, andanhydrous dibasic calcium phosphate, can be used in addition or insteadof the water soluble fillers. The total weight percentage of fillerranges between about 5% and about 75% by weight.

A glidant can be used to improve powder flow properties prior to andduring tabletting and to reduce caking. Suitable glidants includecolloidal silicon dioxide, magnesium trisilicate, powdered cellulose,talc, tribasic calcium phosphate, and the like. Colloidal silicondioxide is preferably included as a glidant in an amount up to about 2%,preferably about 0.2% to about 0.8%, by weight of the tablet.

A lubricant can be used to enhance release of a tablet from apparatus onwhich it is formed, for example by preventing adherence to the face ofan upper punch (“picking”) or lower punch (“sticking”). Suitablelubricants include magnesium stearate, calcium stearate, canola oil,glyceryl palmitostearate, hydrogenated vegetable oil, magnesium oxide,mineral oil, poloxamer, polyethylene glycol, polyvinyl alcohol, sodiumbenzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid,talc, hydrogenated vegetable oil, zinc stearate, and the like. In oneembodiment, magnesium stearate is included as a lubricant in an amountof about 0.1% to about 1.5%, preferably about 0.3% to about 1%, byweight of the tablet.

Among the optional formulating agents that further may be comprised inthe matrix formulation there may be mentioned agents such as polyvidone;copovidone; starch; acacia; gelatin; seaweed derivatives, e.g., alginicacid, sodium and calcium alginate; cellulose, preferablymicrocrystalline cellulose, cellulose derivatives, e.g., ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,having useful dry or wet binding and granulating properties; andantiadherents such as talc and magnesium stearate.

According to a preferred embodiment of the present invention the matrixof the extended release tablet formulation of alternative a) comprisesor essentially consists of pregelatinized starch, hydroxypropyl methylcellulose and excipients. The amount of pregelatinized starch ispreferably in the range from 10 to 75%, particularly preferred from 25to 65% most preferred from 45 to 55% by weight. The amount ofhydroxypropyl methyl cellulose is preferably in the range from 10 to75%, particularly preferred from 25 to 65% most preferred from 35 to 55%by weight. The amount of further excipients is preferably in the rangefrom 0 to 30%, particularly preferred from 0.5 to 20%, most preferredfrom 1 to 10% by weight. Optionally carboxymethyl cellulose sodium mayadditionally be present preferably in the range from 5 to 50,particularly preferred from 10 to 40, most preferred from 15 to 30% byweight.

The expression “consisting essentially” is understood in the sense thatit does not in principle exclude the presence, in addition to themandatory components mentioned, of other components, the presence ofwhich does not affect the essential nature of the formulation.

In case of formulation b) of the present invention it is provided apH-dependent release profile, the release of pramipexole or its saltfrom the tablet and subsequent the absorption into the blood stream canvary during the passage of the dosage form along the gastrointestinaltract. Thus, it is provided a pH-dependent release characteristicwherein the release characteristic in the range of pH<4.5 is faster anda slower and further on pH-independent release characteristic in therange from 4.5≦pH≦7.5.

The above details for the water swelling polymer and selection and typeof optional excipients apply to formulation b), too.

Moreover, an anionic water swelling polymer, preferably an acrylic acidpolymerisate, is mandatorily present in formulation b), which ispreferably selected from carbomer or CARBOPOL® series, known acrylicacid polymerisates having high molecular weights. Particularly preferredare, for example, carbomer 941 (CARBOPOL® 71 G, CARBOPOL® 971) andcarbomer 934 (CARBOPOL® 974). The acrylic acid polymerisate ispreferably present in the range of 0.25 to 25% by weight, particularlypreferred 0.5 to 15% by weight, most preferred 1 to 10% by weight. ThepH dependency of formulation b) results form the presence of acrylicacid polymerisate which intends to swell in a greater extent in the acidpH range above pH 4.5 and in the alkaline pH range. An increasing amountof acrylic acid leads to a decrease of the release rate. Therefore,adjusting the amount of acrylic acid polymerisate makes it possible tofurther tune the dissolution profiles as desired. To adjust the amountof acrylic acid polymerisate in the preferred range from 0.25 to 25% byweight provides the further advantage that the desired, resp. matching,dissolution profiles can be adjusted, resp. maintained, for a variety offormulations composed of different amounts and/or types of gel-formingagents, water swelling polymers, fillers, and dry binders.

According to a preferred embodiment of the present invention the matrixof the extended release tablet formulation of alternative b) comprisesor essentially consists of pregelatinized starch, hydroxypropyl methylcellulose acrylic acid polymerisate and excipients. The amount ofpregelatinized starch is preferably in the range from 10 to 75%,particularly preferred from 25 to 65% most preferred from 45 to 55% byweight. The amount of hydroxypropyl methyl cellulose is preferably inthe range from 10 to 75, particularly preferred from 25 to 65, mostpreferred from 35 to 55% by weight. The amount of acrylic acidpolymerisate is preferably as abovementioned. The amount of excipientsis preferably in the range from 0 to 30 particularly preferred from 0.5to 20, most preferred from 1 to 10% by weight. Optionally carboxymethylcellulose sodium may additionally be present preferably in the rangefrom 5 to 50, particularly preferred from 10 to 40, most preferred from15 to 30% by weight.

As active ingredient, pramipexole or a pharmaceutically acceptable saltthereof, may be present in the formulation according to the presentinvention in any amount suitable for the desired treatment of a patient.A preferred salt of pramipexole is the dihydrochloride salt, mostpreferably in the form of the monohydrate. Usual amounts are from about0.1 to about 5 mg pramipexole salt. According to a particularlypreferred embodiment, e.g., 0.750 mg pramipexole dihydrochloridemonohydrate, corresponding to 0.524 mg anhydrous base, is used in theextended release tablet formulation according to the present invention.However, any other amount of active ingredient suitable for treatmentmay be used with the only proviso that the amount of pramipexole or saltis sufficient to provide a daily dose in one to a small plurality, forexample one to about 4, of tablets to be administered at one time.Preferably the full daily dose is delivered in a single tablet. Anamount of pramipexole salt, expressed as pramipexole dihydrochloridemonohydrate equivalent, of about 0.1 to about 10 mg per tablet, or about0.05% to about 5% by weight of the composition, will generally besuitable. Preferably an amount of about 0.2 to about 6 mg, morepreferably an amount of about 0.3 to about 5 mg, per tablet is present.Specific dosage amounts per tablet, e.g., include 0.375, 0.5, 0.75, 1.0,1.5, 3.0, and 4.5 mg pramipexole dihydrochloride monohydrate. The amountthat constitutes a therapeutically effective amount varies according tothe condition being treated, the severity of the condition, and thepatient being treated.

An extended release tablet formulation according to the presentinvention, has preferably the following composition:

-   -   0.05 to 5% by weight of pramipexole or a salt thereof;    -   10 to 75% by weight of pregelatinized starch;    -   10 to 75% by weight of other water swelling polymer(s);    -   0 to 25% by weight of acrylic acid polymerisate; and    -   to 100% by weight of optional excipient(s).

Therefore, a particularly preferred extended release tablet formulationof the present invention consists of:

-   -   0.1 to 2% by weight of pramipexole or a salt thereof;    -   25 to 65% by weight of hydroxypropyl methyl cellulose;    -   0 to 40% by weight of carboxymethyl cellulose sodium;    -   25 to 75% by weight of pregelatinized starch;    -   0 to 15% by weight of acrylic polymerisate, preferably carbomer        941; and    -   0.5 to 50% by weight of further excipients, preferably selected        from the group consisting of colloidal silicon dioxide,        magnesium stearate, lactose monohydrate, mannitol,        microcrystalline cellulose, dibasic anhydrous calcium phosphate,        hydroxypropyl cellulose, povidone, copovidone, talc, macrogols,        sodium dodecylsulfate, iron oxides, and titanium dioxide.

A starch having a tensile strength of at least about 0.15 kN cm⁻² at asolid fraction representative of the tablet as claimed according to WO2004/010997 is not necessary to practice the present invention.

It is particularly preferred that no coating is present on the tabletformulation according to the present invention. However, the extendedrelease tablet of the invention may comprise a nonfunctional coating. Anonfunctional coating can comprise a polymer component, for exampleHPMC, optionally with other ingredients, for example one or moreplasticizers, colorants, etc. The term “nonfunctional” in the presentcontext means having no substantial effect on release properties of thetablet, and the coating serves another useful purpose. For example, sucha coating can impart a distinctive appearance to the tablet, provideprotection against attrition during packaging and transportation,improve ease of swallowing, and/or have other benefits. A nonfunctionalcoating should be applied in an amount sufficient to provide completecoverage of the tablet. Typically an amount of about 1% to about 10%,more typically an amount of about 2% to about 5%, by weight of thetablet as a whole, is suitable.

The tablets of the present invention can be of any suitable size andshape, for example round, oval, polygonal or pillow-shaped, andoptionally bear nonfunctional surface markings. According to the presentinvention it is preferred that the extended release tablets are white tooff-white and of oval or round, biconvex, shape.

Tablets of the invention can be packaged in a container, accompanied bya package insert providing pertinent information such as, for example,dosage and administration information, contraindications, precautions,drug interactions, and adverse reactions.

The present invention is further directed to the use of the extendedrelease tablet formulation according to the present invention forpreparing a medical composition for the treatment of Parkinson's Diseaseand complications or disorders associated therewith.

Furthermore, the present invention is preferably directed to a method ofmanufacturing the extended release tablet formulations via a diretcompression process comprising the steps of:

-   -   (1) producing an active ingredient trituration wherein the        active ingredient is pramipexole or a pharmaceutically        acceptable salt thereof by preblending it with a portion of        water swelling polymer(s) and/or further excipient(s) in a        mixer, wherein pramipexole or the pharmaceutically acceptable        salt thereof is milled, preferably peg-milled, prior to use;    -   (2) premixing the active ingredient trituration of step (1), the        main portion of the water swelling polymer(s) and/or excipients        in a mixer to obtain a pre-mixture;    -   (3) optionally dry screening the pre-mixture through a screen in        order to segregate cohesive particles and to improve content        uniformity;    -   (4) mixing the pre-mixture of step (2) or (3) in a mixer,        optionally by adding remaining excipients to the mixture and        continuing mixing; and    -   (5) tabletting the final mixture by compressing it on a suitable        tablet press to produce matrix tablets.

Therefore, the tablets are manufactured via a direct compression processwhich applies to both types of pramipexole extended release matrixtablets. To achieve adequate content uniformity in this low drug loadformulation, the active ingredient is preferably peg-milled. Preferablythe particle size distribution of the peg-milled drug substance, asdetermined by laser diffractometry using a dry dispensing system, ischaracterized by particle fraction of 90% (V/V) being smaller than 100μm, most preferably a particle fraction of 90% (V/V) being smaller than75 μm in diameter.

Also other processes can be applied to the manufacturing of pramipexoleextended release tablets, like conventional wet granulation and rollercompaction. In case of wet granulation, preferably pramipexole isgranulated with suitable fillers, like, e.g., starch, microcrystallinecellulose, lactose monohydrate, or anhydrous dibasic calcium phosphate,and wet binding agents, like, e.g., hydroxypropyl methyl cellulose,hydroxypropylcellulose, povidone, copovidone, and starch paste, leadingto a active ingredient concentrate, which after drying and dry screeningis mixed with the main fraction of gel forming excipients, like all theabove described retarding principles. In case of roller compaction, orin other words dry granulation, either a premix of pramipexole with partof the excipients used in the direct compression process, or thecomplete mixture containing all excipients, is processed through aconventional roller compactor to form ribbons, which are thereafterscreened down to granules which are further finally mixed with otherexcipients, like glidants, lubricants, and antiadherents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flow diagram illustrating a preferred embodiment of thedirect compression manufacturing process according to the presentinvention;

FIG. 2 is a graph illustrating the dissolution profiles of a matrixtablet formulation according to the present invention which contains 4%by weight CARBOPOL® in 3 different pH media; and

FIG. 3 is a graph illustrating the dissolution profiles of 3 matrixtablet formulations according to the present invention which contain 0%,1%, and 4% by weight of CARBOPOL®, respectively.

FIG. 1 illustrates a preferred embodiment of the manufacturing processwith reference to a flow diagram wherein the manufacture of the extendedrelease tablets of Examples 1 and 2 are exemplarily shown. FIG. 1 showsthe detailed process steps and the in process controls performed.

Process step (1) is directed to the active ingredient trituration, i.e.,in the present case a salt of pramipexole, pramipexole dihydrochloridemonohydrate, in peg-milled quality, is preblended with a portion of thewater swelling polymer, in this case pregelatinized starch, in acommonly known mixer. In the flow chart a TURBULA® free-fall mixer orblender is used. The mixing time is several minutes, in the present casepreferably 10 minutes.

In process step (2) according to the flow chart, a premixing isperformed, wherein the active ingredient trituration and the mainportion of the water swelling polymer(s) and excipients are premixed forseveral minutes to obtain a pre-mix. In the present case hydroxypropylmethyl cellulose (hypromellose), the main portion of pregelatinizedstarch, carbomer 941 and colloidal silicon dioxide are premixed for 5minutes in the abovementioned TURBULA® mixer or blender.

According to the following process step (3), a dry screening mayoptionally take place. The pre-mixture may be manually screened througha screen, for example a 0.8 mm mesh size screen, in order to segregatecohesive particles and to improve content uniformity.

In the subsequent process step (4), the main mixing step is performedaccording to which the components are mixed for several minutes,preferably 5 minutes in the TURBULA® mixer after screening. Optionallyfurther excipients may be added at this time, in the flow chart thecomponent magnesium stearate is added to the main mixture, and furthermixing for several minutes, e.g., 3 minutes, in the TURBULA® mixer isperformed (final mixing) to obtain the final mixture.

Process step (5) of the process according to the present invention isthe tabletting. The final mixture is compressed on a suitable tabletpress to produce, for example, oblong shaped matrix tablets (extendedrelease tablets or ER tablets). In order to control and maintain therequired quality the obtained matrix tablets are subjected to thefollowing in-process controls: tablet mass, hardness, tablet height, andfriability.

The obtained pramipexole extended release tablets of the presentinvention may then be filled, for example, into High DensityPolyethylene (HDPE) bottles. The bottles are closed tightly with screwcaps and appropriately labeled, whereby all packaging and labelingactivities are performed according to cGMP regulations. Alternatively, ablister type packaging can be used, e.g., using aluminum/aluminum foilblisters.

FIG. 2 represents a graph illustrating the dissolution profiles of amatrix tablet formulation according to the present invention. The matrixtablet contains 4% by weight CARBOPOL®, the detailed composition isgiven in Example 2 and corresponds to the abovementioned formulationaccording to the present invention. The release characteristics of thematrix tablet in 3 different pH media are shown, i.e., in 0.05 Mphosphate buffer, pH=6.8, n=x, in simulated gastric juice, pH=1.2, n=x,and in Mcllvaine buffer, pH=4.5, n=x; (x . . . represents the number ofunits tested). The value percent of released active ingredient isplotted against the time (hours).

FIG. 3 represents a graph illustrating the dissolution profiles of 3matrix tablet formulations according to the present invention. Thematrix tablets contain no CARBOPOL®, 1% or 4% by weight CARBOPOL®,respectively, the detailed compositions are given in Examples 1, 2, and4. The medium is a 0.05 M phosphate buffer, pH=6.8. The value percent ofreleased active ingredient is plotted against the time (hours).

FIGS. 2 and 3 show a pH-independent in vitro release characteristic inthe range from pH 1 to 7.5 in case CARBOPOL® is not present and apH-dependent release characteristic wherein the release characteristicin the range of pH<4.5 is faster in case CARBOPOL® is present. Anincrease of the amount of CARBOPOL® leads to a decreased releasing rate.

The advantages of the present invention are manifold:

According to the present invention extended release tablets containingpramipexole or its salt are available showing different in vitro releaseprofiles. It is possible to select a tailor-made release characteristicfor patient's needs, symptoms, and clinical picture observed.

The primary indication for pramipexole, Parkinson's Disease, is anaffliction that becomes more prevalent with advancing age and is oftenaccompanied by decline in memory. Therefore, the matrix tabletsaccording to the present invention providing an extended or slow releaseof pramipexole or a salt thereof allows to simplify the patient'sadministration scheme by reducing the amount of recommended dailyintakes and improves patient's compliance, particularly relevant forelderly patients. The inventive extended release tablet formulationprovides a daily dose preferably administered at one time.

Furthermore, the tablets of the present invention may be manufacturedvia a direct compression, wet or dry granulation process which appliesto both types of extended release matrix tablets.

The invention described will now be illustrated by the Examples whichfollow various other embodiments and will become apparent to the skilledperson from the present specification. However, it is expressly pointedout that the Examples and description are intended solely as anillustration and should not be regarded as restricting the invention.

EXAMPLES

According to the present invention pramipexole extended release tabletshave been manufactured. The tablets of the Examples are white tooff-white, 14×6.8 mm oblong shaped, biconvex tablets. The tablets areintended to be administered orally, and shall not be divided intohalves. The pramipexole tablets in the Examples contain 0.75 mg ofpramipexole dihydrochloride monohydrate, corresponding to 0.524 mg ofpramipexole free, anhydrous base.

Example 1

One embodiment of the qualitative and quantitative composition ofpramipexole extended release tablets according to the present inventionis shown in Table 1. TABLE 1 Qualitative and Quantitative Composition ofPramipexole Extended Release Tablet mg per 0.75 Reference to Ingredientmg tablet Function Standards Pramipexole dihydrochloride 0.750 ActiveCorporate monohydrate, peg-milled ingredient standard Hypromellose 2208157.500 Swelling Ph.Eur./USP (Methocel K 15 M) agent Pregelatinizedstarch 185.100 Filler Ph.Eur./NF (Starch 1500) Carbomer 941 3.500Gelling Ph.Eur./NF (CARBOPOL ® 71 G) agent Colloidal silicon dioxide1.400 Glidant Ph.Eur./NF Magnesium stearate 1.750 Lubricant Ph.Eur./NFTotal 350.000

Example 2

A further embodiment of the qualitative and quantitative composition ofpramipexole extended release tablets according to the present inventionis shown in Table 2. TABLE 2 Qualitative and Quantitative Composition ofPramipexole Extended Release Tablet mg per 0.75 Reference to Ingredientmg tablet Function Standards Pramipexole dihydrochloride 0.750 ActiveCorporate monohydrate, peg-milled ingredient standard Hypromellose 2208157.500 Swelling Ph.Eur./USP (Methocel K 15 M) agent Pregelatinizedstarch 174.600 Filler Ph.Eur./NF (Starch 1500) Carbomer 941 14.000Gelling Ph.Eur./NF (CARBOPOL ® 71 G) agent Colloidal silicon dioxide1.400 Glidant Ph.Eur./NF Magnesium stearate 1.750 Lubricant Ph.Eur./NFTotal 350.000

Example 3

The batch formula for the two pramipexole tablet formulations of Example1 and 2 is shown in Table 3. The batch size of the final mixturecorresponds to a batch size of 2000 tablets. TABLE 3 Composition perBatch of Pramipexole 0.75 mg ER Tablets Grams per Grams per batch batchIngredient Example 1 Example 2 Pramipexole dihydrochloride 1.500 1.500monohydrate, peg-milled Hypromellose 2208 315.000 315.000 Pregelatinizedstarch 370.200 349.200 Carbomer 941 7.000 28.000 Colloidal silicondioxide 2.800 2.800 Magnesium stearate 3.500 3.500 Total Mass 700.000700.000

Example 4

The following Example shows a pramipexole tablet formulation whichcorresponds to formulation a) providing a release characteristicindependent in the pH range of 1 to 7.5. TABLE 4 Constituents mg/tabletPramipexole dihydrochloride 0.750 monohydrate, peg-milled Hypromellose2208 (Methocel K 100 M) 175.000 Pregelatinized starch 170.400 Colloidalsilicon dioxide 2.100 Magnesium stearate 1.750 Total weight matrixtablet 350.000

1. An extended release tablet formulation comprising pramipexole or apharmaceutically acceptable salt thereof in a matrix comprising: (a)pregelatinized starch; and (b) an anionic polymer.
 2. The extendedrelease tablet formulation according to claim 1, wherein the anionicpolymer is selected from the group consisting of optionally crosslinkedacrylic acid polymers, methacrylic acid polymers, alginates, andcarboxymethyl cellulose.
 3. The extended release tablet formulationaccording to claim 2, wherein the anionic polymer is an optionallycrosslinked acrylic acid polymer, and wherein the content of theoptionally crosslinked acrylic acid polymer in the matrix is from about0.25 wt.-% to about 25 wt.-%.
 4. The extended release tablet formulationaccording to claim 3, wherein the anionic polymer is an optionallycrosslinked acrylic acid polymer, and wherein the content of theoptionally crosslinked acrylic acid polymer in the matrix is from about0.5 wt.-% to about 15 wt.-%.
 5. The extended release tablet formulationaccording to claim 4, wherein the anionic polymer is an optionallycrosslinked acrylic acid polymer, and wherein the content of theoptionally crosslinked acrylic acid polymer in the matrix is from about1 wt.-% to about 10 wt.-%.
 6. The extended release tablet formulationaccording to claim 1, further comprising a water swelling polymer whichis not pregelatinized starch or an anionic polymer.
 7. The extendedrelease tablet formulation according to claim 6, wherein the waterswelling polymer which is not pregelatinized starch or an anionicpolymer is hydroxypropyl cellulose or hydroxypropyl methyl cellulose. 8.The extended release tablet formulation according to claim 7, whereinthe water swelling polymer which is not pregelatinized starch or ananionic polymer is hydroxypropyl methyl cellulose.
 9. The extendedrelease tablet formulation according to claim 8, wherein the content ofhydroxypropyl methyl cellulose in the matrix is from about 10 wt.-% toabout 75 wt.-%.
 10. The extended release tablet formulation according toclaim 9, wherein the content of hydroxypropyl methyl cellulose in thematrix is from about 25 wt.-% to about 65 wt.-%.
 11. The extendedrelease tablet formulation according to claim 1, wherein the matrixcomprises about: (a) 0.05 to 5 wt.-% of pramipexole or a salt thereof;(b) 0.25 to 25 wt.-% of anionic water swelling polymer(s); (c) 10 to 75wt.-% of water swelling polymer(s) other than (b); and (d) to 100 wt.-%of further excipients.
 12. An extended release tablet formulationcomprising pramipexole or a pharmaceutically acceptable salt thereof ina matrix comprising: (a) at least pregelatinized starch as waterswelling polymer and optionally excipients, the resulting tabletproviding a pH-independent in vitro release characteristic in the rangefrom pH 1 to 7.5, or (b) at least pregelatinized starch as waterswelling polymer, a water swelling anionic polymer, and optionallyexcipients, the resulting tablet providing a pH-dependent releasecharacteristic with a faster release characteristic in the range ofpH<4.5, and a slower and further on pH-independent releasecharacteristic in the range from pH 4.5 to 7.5.
 13. The extended releasetablet formulation according to claim 6, wherein the water swellingpolymer which is not pregelatinized starch or an anionic polymer ishydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose sodium, or sodium alginate.
 14. The extended release tabletformulation according to claim 12, wherein the matrix compriseshydroxypropyl methyl cellulose and excipients, wherein the amount ofhydroxypropyl methyl cellulose ranges from 10 to 75% by weight and theamount of excipients ranges from 25 to 90% by weight.
 15. The extendedrelease tablet formulation according to claim 12, wherein the matrixcomprises hydroxypropyl methyl cellulose and excipients, wherein theamount of hydroxypropyl methyl cellulose ranges from 25 to 65% by weightand the amount of excipients ranges from 35 to 75% by weight.
 16. Theextended release tablet formulation according to claim 1, wherein theanionic polymer is an acrylic acid polymerisate.
 17. The extendedrelease tablet formulation according to claim 16, wherein the acrylicacid polymerisate is present in the range of 0.25 to 25% by weight. 18.The extended release tablet formulation according to claim 17, whereinthe acrylic acid polymerisate is present in the range of 0.5 to 15% byweight.
 19. The extended release tablet formulation according to claim18, wherein the acrylic acid polymerisate is present in the range of Ito 10% by weight.
 20. A method of manufacturing the extended releasetablet formulation by a direct compression process comprising the stepsof: (1) producing an active ingredient trituration wherein the activeingredient is pramipexole or a pharmaceutically acceptable salt thereofby preblending it with a portion of water swelling polymer(s) and/orexcipient(s) in a mixer, wherein pramipexole or the pharmaceuticallyacceptable salt thereof is milled prior to use; (2) premixing the activeingredient trituration of step (1), the main portion of the waterswelling polymer(s), and/or excipients in a mixer to obtain apre-mixture; (3) optionally dry screening the pre-mixture through ascreen in order to segregate cohesive particles and to improve contentuniformity; (4) mixing the pre-mixture of step (2) or (3) in a mixer,optionally by adding remaining excipients to the mixture and continuingmixing; and (5) tabletting the final mixture by compressing it on asuitable tablet press to produce matrix tablets.
 21. The methodaccording to claim 20, wherein the pramipexole or the pharmaceuticallyacceptable salt thereof is peg-milled prior to use in step (1).
 22. Amethod of manufacturing the extended release tablet formulation by a wetgranulation process comprising the steps of: (1) producing an activeingredient trituration wherein the active ingredient is pramipexole or apharmaceutically acceptable salt thereof by blending it with a portionof the excipients in a mixer, wherein pramipexole or thepharmaceutically acceptable salt thereof is milled prior to use; (2)granulating the active ingredient trituration of step (1) by adding thegranulation liquid; (3) drying the granules of step (2) in a fluidizedbed dryer or a drying oven; (4) mixing the dried granules of step (3)with the water swelling polymer(s) and/or excipients in a mixer toobtain the final mixture; (5) tabletting the final mixture of step (4)by compressing it on a suitable tablet press to produce matrix tablets.23. The method according to claim 22, wherein the pramipexole or thepharmaceutically acceptable salt thereof is peg-milled prior to use instep (1).
 24. The method according to claim 22, wherein the granulationliquid of step (2) is water.
 25. A method of manufacturing the extendedrelease tablet formulation by a dry granulation process comprising thesteps of: (1) mixing the active ingredient pramipexole or apharmaceutically acceptable salt thereof with either a portion of thefillers or all the excipients in a mixer, wherein pramipexole or thepharmaceutically acceptable salt thereof is milled prior to use; (2)compaction of the mixture of step (1) on a suitable roller compactor;(3) reducing the ribbons obtained during step (1) to small granules bysuitable milling or sieving steps; (4) optionally mixing the granules ofstep (3) with the remaining excipients in a mixer to obtain the finalmixture; and (5) tabletting the granules of step (3) or the finalmixture of step (4) by compressing it on a suitable tablet press toproduce matrix tablets.
 26. The method according to claim 25, whereinthe pramipexole or the pharmaceutically acceptable salt thereof ispeg-milled prior to use in step (1).